摘要
背景:阻断c-Met信号和表皮生长因子受体信号通路是否能有效抑制人大肠癌细胞的生长尚不清楚。在这里本研究观察了c-甲基-甲基转移酶抑制剂PHA-665752单独及联合西妥昔单抗对人大肠癌细胞体外和小鼠移植瘤生长的影响。 方法:人大肠癌细胞株(Caco 2、HCT-116、HT-29)和荷HCT-116异种移植小鼠,在不含PHA-665752的情况下,用西妥昔单抗治疗。细胞活力和凋亡分别用MTT法和TUNEL法进行胺化。免疫组化法检测波形蛋白作为上皮向间充质转化的标志.。用Westernblotting法测定信号G蛋白表达水平。 结果:MTT法显示PHA-665752对Caco 2、HCT-116和HT-29细胞的生长具有剂量依赖性抑制作用,而只有Caco 2细胞生长受到西妥昔单抗的抑制。梳状PHA-665752和西妥昔单抗对Caco 2细胞和RAS突变型CRC细胞的增殖有抑制作用。然而,相对于pha-665752单独治疗组,HT-29细胞与胸罩F基因突变效果不明显。头孢妥昔单抗联合pha-665752治疗小鼠的平均肿瘤体积明显小于单用西妥昔单抗的小鼠。(P=0.033)或PHA-665752(P<0.01)。同样,pha-665752联合西妥昔单抗治疗小鼠的波形蛋白表达也明显低于对照组。单用西妥昔单抗或PHA-665752(P<0.05)。TUNEL检测显示,PHA-665752与西妥昔单抗联合治疗可明显增加大肠癌细胞凋亡。Westernblotting分析信号蛋白表达的SIS显示PHA-665752抑制Met磷酸化(P<0.05)。此外,单用西妥昔单抗治疗或联合pha-665752有效抑制。d EGFR磷酸化(P<0.05)。 结论:PHA-665752和西妥昔单抗联合治疗对大肠癌细胞的体外和体内生长抑制作用均大于单独用药对CRC细胞生长的抑制作用。
关键词: 大肠癌,西妥昔单抗、RAS、BRAF、c-Met、结直肠癌细胞株。
图形摘要
Current Cancer Drug Targets
Title:Effects of PHA-665752 and Cetuximab Combination Treatment on In Vitro and Murine Xenograft Growth of Human Colorectal Cancer Cells with KRAS or BRAF Mutations
Volume: 18 Issue: 3
关键词: 大肠癌,西妥昔单抗、RAS、BRAF、c-Met、结直肠癌细胞株。
摘要: Background: It remains unknown whether blockade of c-Met signaling and epidermal growth factor receptor signaling is effective in suppressing the growth of human colorectal cancer (CRC) cells. In this study, we investigated the effects of the c-Met inhibitor PHA-665752 alone and in combination with cetuximab on the growth of human CRC cells in vitro and in mouse xenografts.
Methods: Human CRC cell lines (Caco2, HCT-116, and HT-29) and mice bearing HCT-116 xenografts were treated with cetuximab in the absence or presence of PHA-665752. Cell viability and apoptosis were examined using the MTT and TUNEL assays, respectively. Vimentin was measured by immunohistochemistry as a marker for epithelial-to-mesenchymal transition. Western blotting was used to determine signaling protein expression levels.
Results: The MTT assay showed that the growth of Caco2, HCT-116, and HT-29 cells was inhibited by PHA-665752 in a dose-dependent manner, but only Caco2 cell growth was suppressed by cetuximab. Combination treatment with PHA-665752 and cetuximab inhibited the proliferation of Caco2 cells and RAS mutant CRC cell lines. However, relative to the PHA-665752-alone treatment group, HT-29 cells with a BRAF mutation showed no noticeable effect. The mean tumor volume in mice treated with cetuximab in combination with PHA-665752 was significantly smaller than that in the mice treated with only cetuximab (P = 0.033) or PHA-665752 (P < 0.01). Similarly, the expression of vimentin in the mice treated with PHA-665752 in combination with cetuximab was significantly lower than that in the mice treated with cetuximab or PHA-665752 alone (P < 0.05 in each case). TUNEL assays revealed that treatment with PHA-665752 in combination with cetuximab markedly increased CRC cell apoptosis. Western blotting analysis of signaling protein expression showed that PHA- 665752 inhibited Met phosphorylation (P < 0.05). In addition, treatment with cetuximab alone or in combination with PHA-665752 effectively inhibited EGFR phosphorylation (P < 0.05).
Conclusion: Combination treatment with PHA-665752 and cetuximab suppressed in vitro and in vivo CRC cell growth more than treatment with either agent alone did.
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Cite this article as:
Effects of PHA-665752 and Cetuximab Combination Treatment on In Vitro and Murine Xenograft Growth of Human Colorectal Cancer Cells with KRAS or BRAF Mutations, Current Cancer Drug Targets 2018; 18 (3) . https://dx.doi.org/10.2174/1568009617666170330112841
DOI https://dx.doi.org/10.2174/1568009617666170330112841 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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